Benazepril, an Angiotensin‐converting Enzyme Inhibitor, Alleviates Renal Injury in Spontaneously Hypertensive Rats by Inhibiting Advanced Glycation End‐product‐mediated Pathways

Abstract

1. Advanced glycation end-products (AGE) and their receptors (RAGE) have been implicated in renal damage in diabetes. The aim of the present study was to investigate the effects of benazepril, an angiotensin-converting enzyme inhibitor (ACEI), on the formation of AGE, the expression RAGE and other associated components in the oxidative stress pathway in spontaneously hypertensive rats (SHR). 2. Groups of SHR were treated with or without 10 mg/kg per day benazepril for 12 weeks. Systolic blood pressure (SBP) and angiotensin (Ang) II levels were evaluated in SHR and control Wistar-Kyoto (WKY) rats. Renal function was investigated by determining levels of proteinuria and glomerulosclerosis. Furthermore, reactive oxygen species (ROS) in the rat renal cortex were analysed using an H(2)O(2)-based hydroxyl radical-detection assay and the renal content of AGE, RAGE, NADPH oxidase p47phox, nuclear factor (NF)-kappaB p65, phosphorylated (p-) NF-kappaB p65, vascular cell adhesion molecule (VCAM)-1 and transforming growth factor (TGF)-beta1 was determined by immunohistochemistry, quantitative real-time polymerase chain reaction and western blot analysis. 3. Treatment with benazepril inhibited the formation of AngII, reduced SBP and alleviated renal lesions in SHR compared with both untreated SHR and control WKY rats. Benazepril treatment significantly suppressed the accumulation of AGE and expression of RAGE in the kidney of SHR. In addition, benazepril treatment reduced the upregulation of NADPH oxidase p47phox, ROS generation and NF-kappaB p65, p-NF-kappaB p65, VCAM-1 and TGF-beta1 expression in the kidney of SHR compared with both untreated SHR and control WKY rats. 4. The results of the present study provide new insights into the regulation by the renin-angiotensin system of AGE-RAGE, oxidative stress and nephropathy, increasing our understanding of the role of the RAS in nephropathy.

Diabetes mellitus impairs tendon-bone healing after rotator cuff repair

“…Preliminary studies with pharmacological inhibitors of AGE formation and AGE-specific receptors in diabetic animals have proven to be effective in the prevention of retinopathy, nephropathy, and neuropathy. 39,45,58,62 Furthermore, the efficacy of both systemic and local insulin therapy in the perioperative period to control excess sugar accumulation at the healing tendon-bone interface is currently being investigated. Prospective clinical trials in euglycemic and diabetic patients are also necessary to correlate the metabolic state with both structural and functional outcomes after rotator cuff surgery.…”

Tipping the redox balance of oxidative stress in fibrogenic pathways in chronic kidney disease

“…Ang II infusions in NOX1-deficient and p47phox-deficient mice blunted ROS formation and reduced blood pressure [95,96]. Recent studies using AT2 receptor blockers in experimental models of CKD demonstrated decreased levels of ROS production and oxidative stress resulting in attenuated renal injury, providing another anti-fibrotic mechanism for these medications [97][98][99]. A recently published study of mice deficient in angiotensin II type 1 receptor (Agtr1a) demonstrated increased longevity with attenuated vascular and cardiac injury in comparison with that of littermate controls.…”

Fosinopril and Losartan Regulate Klotho Gene and Nicotinamide Adenine Dinucleotide Phosphate Oxidase Expression in Kidneys of Spontaneously Hypertensive Rats

“…Blockade of the RAS with ACEI and/or ARB is currently the best documented treatment strategy to attenuate the progression of hypertensive renal damage [26][27][28] . Therefore, we adopted Fos or Los for intervention in SHR, finding that Fos or Los could decrease blood pressure, NAGase, proteinuria, Scr and BUN, and renal pathological damage.…”